Click chemistry-driven modular radionuclide labeling of HER2 nanobody: An integrated platform for diagnosis and treatment of precision oncology

Current HER2-targeted theranostics lack a unified platform capable of integrating high-resolution PET/SPECT imaging, ¹⁷⁷Lu radionuclide therapy, and personalized dosimetry. To address this, we developed a bioorthogonal "click-to-label" platform​ enabling universal radiolabeling of a single anti-HER2 nanobody (HER2VHH) with four clinically relevant isotopes (¹⁸F, ⁶⁸Ga, ^99mTc, ¹⁷⁷Lu). This trans-cyclooctene (TCO) and tetrazine (Tz)-mediated approach circumvents direct exposure of the fragile nanobody to harsh radiolabeling conditions, thereby preserving its immunoreactivity. Compared to conventional direct labeling, our platform demonstrated significantly enhanced tumor retention and superior imaging contrast, while allowing flexible labeling with various radionuclides. Notably, the ¹⁷⁷Lu-labeled HER2VHH effectively inhibited tumor growth in a dose-dependent manner without detectable off-target toxicity. These findings support ¹⁸F/⁶⁸Ga/^99mTc/¹⁷⁷Lu-TzTCO-HER2VHH as a promising HER2-targeted theranostic platform, combining sensitive PET/SPECT imaging with effective radionuclide therapy, and demonstrating substantial potential for clinical translation in precision oncology.